Nature Communications study lays groundwork for new abdominal aortic aneurysm treatment

Nestled in the wall of the body’s largest blood vessel is a ticking time bomb.

If you’re one of the one in 1,000 people diagnosed with an abdominal aortic aneurysm (AAA), that is.

Aneurysms, or when part of an artery becomes weakened and expands, are as lethal as they are sneaky. Regardless of location, they often present no symptoms until they rupture. Most common in elderly men, it often results in significant morbidity and mortality.

headshots of Amanda Filiberto, Ashish Sharma, and Gilbert Upchurch
Left to right: Drs. Amanda Filiberto, Ashish K. Sharma, and Gilbert R. Upchurch Jr.

Typically, AAA treatment falls into two camps: watchful waiting and surgery. With one nerve-wracking and the other invasive, clinicians have long looked for a third option.

Now, in a new study recently published in Nature Communications, researchers from the University of Florida’s Department of Surgery hope to bring one to the table.

“We wanted to explore the pathophysiology of AAA to better understand them from a mechanistic and therapeutic standpoint,” said Amanda Filiberto, M.D., a fourth-year general surgery resident and first author. “Our goal is for translational research, and what we can bring from the bench to the bedside. The clinical implications of our findings are exciting, and the basic science used cutting edge research methods.”

The authors looked at the role of Pannexin-1 (Panx1) ion channels in AAA. The findings characterized Panx1 channels on endothelial cells as responsible for regulating vascular inflammation and remodeling.

“Typically, endothelial cells are viewed as having a comparatively subtle immunologic role in aneurysmal pathology when compared with smooth muscle cells and macrophages. However, our study provides key insights for the contributory role of endothelial Panx1 channels to regulate aortic inflammation and remodeling to cause aneurysm formation, which increases our fundamental knowledge of this disease process,” said Ashish Sharma, MBBS, Ph.D., corresponding  author and associate professor in the department of surgery.

Currently, there are medications that block Panx1 channels, which are used to treat other diseases. Until now, their use in treatment of AAA has been unknown.

In a true bench-to-bedside study design method, researchers used two mouse models and a retrospective patient study to confirm that when the channels were blocked, it reduced aortic inflammation and aneurysm formation as well as decreased mortality in human patients.

photo of pannexin-1 ion channels
Pannexin-1 ion channels on the aorta.

The study was comprehensive to the nth degree, using multiple experimental murine models, cell cultures, human aortic tissue and the retrospective clinical analysis.

“This is really the first time we’re showing a mechanistic effect relative to these ion channels in this disease process,” Sharma said. “But we’re also seeing that patients on this medication have better outcomes in terms of their overall survival.”

The contribution of Panx1 channel function expands fundamental knowledge of the AAA disease process and could be  a game changer, Sharma said. Before the study, there was no medical treatment to address the vascular disease.

“Clinical translation typically takes a very long time,” said Gilbert R. Upchurch Jr., M.D., vascular surgeon and chair of the department of surgery. “In this case, it is advanced by the use of repurposed drugs, which are currently used in the treatment of other diseases. It’s an exciting discovery, not only because it expands our scientific knowledge, but because it means we can control an inflammatory process in a human body’s largest blood vessel and be used safely in the treatment of this often-fatal disease.”schematic of pannexin

Now, the study offers hope.

“Most individuals with an AAA are asymptomatic, and usually are identified incidentally during a workup for another unrelated pathology,” Filiberto said. “It’s a surprise, and once they are aware, a lot of patients are living with the idea that it could rupture at any time. Our study provides an avenue for new treatment — and peace of mind.”